Generation and Evaluation of KSHV VLPs as Vaccines

KSHV VLP 作为疫苗的生成和评估

• 批准号: 7943952
• 负责人: PRASHANT J DESAI
• 金额: $ 49.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943952
• 关键词: AIDS vaccine development; AIDS with Kaposi' s sarcoma; Acquired Immunodeficiency Syndrome; Address; Africa; Antibodies; Antibody Formation; Antigens; Baculoviruses; Biological; Biological Assay; Biological Models; CD8B1 gene; Cancer Etiology; Capsid; Cell Culture Techniques; Cells; Cellular Immunity; Cervix carcinoma; Collection; Country; Data; Development; Epidemic; Epitopes; Evaluation; Fluorescence; Frequencies; Future; Gays; Generations; Glycoproteins; Goals; HIV; HIV Infections; Herpesviridae; Herpesviridae Infections; Highly Active Antiretroviral Therapy; Human; Human Herpesvirus 8; Human Papillomavirus; Immune; Immune response; Immunoglobulin G; Immunoglobulin M; Immunosuppression; Individual; Infection; Influenza; Insecta; Interferons; Kaposi Sarcoma; Life Style; Malignant Neoplasms; Measurement; Measures; Membrane Glycoproteins; Memory; Modeling; Mus; New York; Oncogenes; Opportunistic Infections; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Population; Preparation; Protein Microchips; Proteins; Proteome; Reagent; Reporting; Research; San Francisco; Serum; Severe Acute Respiratory Syndrome; Shotguns; Simplexvirus; Southern Africa; Staging; Structural Protein; Structure; Subgroup; Subunit Vaccines; Surface; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Titrations; Vaccination; Vaccines; Viral Antibodies; Viral Genome; Viral Proteins; Viral Structural Proteins; Virion; Virus; Virus-like particle; Yeasts; absorption; base; cell mediated immune response; cytokine; design; env Gene Products; expression vector; high throughput screening; human coronavirus; immune function; immunogenicity; influenzavirus; innovation; men; neglect; neutralizing antibody; novel; particle; prevent; prophylactic; public health relevance; reconstitution; response; self assembly; skin lesion; success; therapeutic vaccine; tumor; vaccine development; viral DNA

DESCRIPTION (provided by applicant): This proposal is being submitted in response to the Announcement RFA-OD-09-004 under ARRA Research Grand Opportunities for Exploratory Research in the Development of Vaccines for AIDS-Associated Malignancies (RC2 mechanism). This is designed to stimulate early stage innovative research efforts in either preventative or therapeutic vaccine development for infectious causes of cancer. Kaposi's sarcoma (KS) was one of the original defining opportunistic infections in the AIDS epidemic, when these highly angiogenic skin lesions first appeared in an aggressive often disseminated form in young gay men in New York and San Francisco. In 1994, both classic and epidemic KS were found out to be caused by a previously unknown human herpesvirus called Kaposi's Sarcoma Associated Herpesvirus (KSHV or sometimes HHV8). Today in Southern Africa, KS has become the most prevalent of all tumors because of the spread of HIV into a population that was already nearly universally endemically infected by KSHV. In contrast, in Western countries, KSHV infections are very uncommon, except in AIDS-patients with promiscuous life-style factors, where this combined with HIV-induced immunosuppression produces KS at high frequency. Fortunately, the use of HAART and related therapies has reduced the problem of KS, but there is still a subset of patients with stable reconstituted immune function, in which KS reappears and becomes increasingly non-responsive over time. We believe that preventative vaccines against KSHV should be seriously considered as a potential way to control KSHV infection in Western countries and possibly in future in Africa also. However, little is known as yet about immune responses to KSHV infection in either KS or non-KS patients, and vaccines did not appear attractive previously because of the large size and complexity of this virus, as well as the fact that as a tumor forming virus the viral genome and oncogenes would have to be absent or removed. Based on recent success with prophylactic HPV subunit vaccines to prevent cervical carcinoma, and the demonstration that virus-like particles (VLP) of small viruses such as influenza can be effective in inducing a variety of immune responses, the vaccine prospects for other AIDS malignancies now need to be reassessed. Here we propose initial exploratory steps to both develop a DNA-free VLP-based preventative vaccine for KSHV/KS, and to develop a revolutionizing high-throughput global proteome approach to measuring viral antibody and neutralization responses in KSHV-positive patients with and without KS, as well as the responses induced by VLP vaccination. These will be assessed in experimental inocculated mice, as well as in existing collections of AIDS and KS patient sera. The global proteome approach has the additional advantage of not only likely providing much new data discovery about novel KSHV antigens and epitopes, but also potentially of being used as a Pan-herpesvirus immune assessment test chip for both humoral and T-cell mediated immunity in all relevant patients. PUBLIC HEALTH RELEVANCE: Narrative: This project responds to an RFA OD-09-004 for early exploratory research on the development of vaccines for AIDS Malignancies. We propose to attempt to assemble in insect cell culture DNA-free virus-like particles (VLP) as potential preventative vaccines against Kaposi's sarcoma, which is caused by the herpesvirus KSHV. The immune responses to these experimental VLP will be assessed with the first steps in development of an innovative new global high-throughput assay approach for identifying and measuring viral proteins as targets for humoral (neutralizing antibodies) and T-cell-mediated immune responses to KSHV and other human herpesviruses in AIDS patients.

描述（由申请人提供）：该提案是根据ARRA研究开发艾滋病相关恶性肿瘤疫苗的探索性研究重大机会（RC2机制）下的公告RFA-OD-09-004提交的。这一计划的目的是刺激针对癌症传染性原因的预防性或治疗性疫苗开发的早期创新研究工作。卡波西肉瘤（KS）是艾滋病流行中最早定义的机会性感染之一，当这些高度血管生成的皮肤病变首次出现在纽约和旧金山的年轻男同性恋者身上时，通常以侵袭性的弥散形式出现。1994年，经典KS和流行KS都被发现是由一种以前未知的人类疱疹病毒引起的，这种病毒被称为卡波西肉瘤相关疱疹病毒（KSHV，有时也称为HHV8）。今天在南部非洲，KS已经成为所有肿瘤中最普遍的，因为艾滋病毒传播到已经几乎普遍感染KSHV的人群中。相比之下，在西方国家，KSHV感染非常罕见，除了生活方式因素混杂的艾滋病患者，这种情况与hiv诱导的免疫抑制相结合，产生KS的频率很高。幸运的是，HAART和相关疗法的使用减少了KS的问题，但仍有一部分患者具有稳定的重建免疫功能，其中KS再次出现并随着时间的推移变得越来越无反应。我们认为，应该认真考虑对KSHV的预防性疫苗作为控制西方国家和非洲未来可能的KSHV感染的潜在方法。然而，对于KS或非KS患者对KSHV感染的免疫反应知之甚少，而且由于这种病毒的体积大且复杂，以及作为一种形成肿瘤的病毒，病毒基因组和致癌基因必须缺失或去除，以前疫苗似乎没有吸引力。基于最近预防性HPV亚单位疫苗预防宫颈癌的成功，以及流感等小病毒的病毒样颗粒（VLP）可有效诱导各种免疫反应的证明，现在需要重新评估其他艾滋病恶性肿瘤的疫苗前景。在这里，我们提出了初步的探索性步骤，以开发一种无dna的基于VLP的KSHV/KS预防性疫苗，并开发一种革命性的高通量全球蛋白质组方法来测量KSHV阳性和非KS患者的病毒抗体和中和反应，以及VLP接种诱导的反应。这些将在实验性接种的小鼠以及现有的艾滋病和KS患者血清中进行评估。全局蛋白质组学方法具有额外的优势，不仅可能提供许多关于新的KSHV抗原和表位的新数据发现，而且还可能被用作泛疱疹病毒免疫评估测试芯片，用于所有相关患者的体液和t细胞介导免疫。